`
`(12) United States Patent (cid:9)
`Acheampong et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 8,648,048 B2
`*Feb. 11, 2014
`
`(54) METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`Inventors: Andrew Acheampong, Irvine, CA (US);
`Diane D. Tang-Liu, Las Vegas, NV
`(US); James N. Chang, Newport Beach,
`CA (US); David F. Power, Hubert, NC
`(US)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`* )
`
`Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/967,168
`
`(22) Filed:
`
`Aug. 14, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0331340 Al (cid:9)
`
`Dec. 12, 2013
`
`Related U.S. Application Data
`
`DE
`EP
`
`5,296,158
`5,342,625
`5,368,854
`5,411,952
`5,424,078
`5,474,919
`5,474,979
`5,504,068
`5,540,931
`5,543,393
`5,589,455
`5,591,971
`5,614,491
`5,639,724
`5,652,212
`5,719,123
`5,739,105
`5,753,166
`5,766,629
`5,798,333
`5,807,820
`5,827,822
`5,827,862
`5,834,017
`5,843,452
`5,843,891
`5,858,401
`5,866,159
`
`3/1994
`MacGilp et al.
`8/1994
`Hauer et al.
`11/1994
`Rennick
`5/1995
`Kaswan
`6/1995
`Dziabo
`12/1995
`Chartrain et al.
`12/1995
`Ding et al.
`4/1996
`Komiya et al.
`7/1996
`Hewitt et al.
`8/1996
`Kim et al.
`12/1996
`Woo
`1/1997
`Shahar et al.
`3/1997
`Walch et al.
`6/1997
`Cavanak
`7/1997
`Cavanak et al.
`2/1998
`Morley et al.
`4/1998
`Kim et al.
`5/1998
`Dalton et al.
`6/1998
`Cho et al.
`8/1998
`Sherman
`9/1998
`Elias et al.
`10/1998
`Floch'h et al.
`10/1998
`Yamamura
`11/1998
`Cho et al.
`12/1998
`Wiedmann et al.
`12/1998
`Sherman
`1/1999
`Bhalani et al.
`2/1999
`Hauer et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`9/1999
`19810655 (cid:9)
`2/1992
`0471293 (cid:9)
`(Continued)
`
`OTHER PUBLICATIONS
`
`(63) Continuation of application No. 13/961,835, filed on
`Aug. 7, 2013, which is a continuation of application
`No. 11/897,177, filed on Aug. 28, 2007, which is a
`continuation of application No. 10/927,857, filed on
`Aug. 27, 2004, now abandoned.
`
`(60) Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(2006.01)
`
`(51) Int. Cl.
`A61K 38/13 (cid:9)
`(52) U.S. Cl.
`USPC (cid:9)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
` 514/20.5
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,278,447 A (cid:9)
`4,388,229 A (cid:9)
`4,388,307 A (cid:9)
`4,614,736 A (cid:9)
`4,649,047 A (cid:9)
`4,764,503 A (cid:9)
`4,814,323 A (cid:9)
`4,839,342 A (cid:9)
`4,970,076 A (cid:9)
`4,990,337 A (cid:9)
`4,996,193 A (cid:9)
`5,047,396 A (cid:9)
`5,051,402 A (cid:9)
`5,053,000 A (cid:9)
`5,286,730 A (cid:9)
`5,286,731 A (cid:9)
`5,294,604 A (cid:9)
`
`10/1966
`6/1983
`6/1983
`9/1986
`3/1987
`8/1988
`3/1989
`6/1989
`11/1990
`2/1991
`2/1991
`9/1991
`9/1991
`10/1991
`2/1994
`2/1994
`3/1994
`
`McNicholas
`Fu
`Cavanak
`Delevallee et al.
`Kaswan
`Wenger
`Andrieu et al.
`Kaswan
`Horrobin
`Kurihara et al.
`Hewitt et al.
`Orban et al.
`Kurihara et al.
`Booth et al.
`Caufield et al.
`Caufield et al.
`Nussenblatt et al.
`
`Abdulrazik, M. et al, Ocular Delivery of Cyclosporin A II. Effect of
`Submicron Emulsion's Surface Charge on Ocular Distribution of
`Topical Cyclosporin A, S.T.P. Pharma Sciences, Dec. 2001, 427-432,
`11(6).
`Acheampong, Andrew et al, Cyclosporine Distribution into the Con-
`junctiva, Cornea, Lacrimal Gland and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog and Human eyes,
`1996, 179.
`Acheampong, Andrew et al, Cyclosporine Distribution Into the Con-
`junctiva, Cornea, Lacrimal Gland, and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog, and Human Eyes,
`Adv. Exp. Med. Biol., 1998, 1001-1004, 438.
`Acheampong, Andrew et al, Distribution of Cyclosporin A in Ocular
`Tissues After Topical Administration to Albino Rabbits and Beagle
`Dogs, Current Eye Research, 1999, 91-103, 18(2).
`
`(Continued)
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm Laura L. Wine; Joel B.
`German; Debra D. Condino
`
`ABSTRACT
`(57) (cid:9)
`Methods of treating an eye of a human or animal include
`administering to an eye of a human or animal a composition
`in the form of an emulsion including water, a hydrophobic
`component and a cyclosporin component in a therapeutically
`effective amount of less than 0.1% by weight of the compo-
`sition. The weight ratio of the cyclosporin component to the
`hydrophobic component is less than 0.8.
`
`23 Claims, No Drawings
`
` EXHIBIT 1001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`
`
`US 8,648,048 B2
`Page 2
`
`(56) (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,891,846 A
`5,916,589 A
`5,929,030 A
`5,951,971 A
`5,962,014 A
`5,962,017 A
`5,962,019 A
`5,977,066 A
`5,981,479 A
`5,981,607 A
`5,998,365 A
`6,004,566 A
`6,007,840 A
`6,008,191 A
`6,008,192 A
`6,022,852 A
`6,024,978 A
`6,046,163 A
`6,057,289 A
`6,159,933 A
`6,197,335 Bl
`6,254,860 Bl
`6,254,885 Bl
`6,267,985 Bl
`6,284,268 B1
`6,294,192 Bl
`6,306,825 Bl
`6,323,204 Bl
`6,346,511 Bl
`6,350,442 B2
`6,413,547 Bl
`6,420,355 B2
`6,468,968 B2
`6,475,519 Bl
`6,486,124 B2
`6,544,953 B2
`6,555,526 B2
`6,562,873 B2
`6,569,463 B2
`6,582,718 B2
`6,656,460 B2
`6,872,705 B2
`6,984,628 B2 *
`7,202,209 B2
`7,276,476 B2
`7,288,520 B2
`7,297,679 B2
`7,501,393 B2
`8,211,855 B2
`8,288,348 B2
`2001/0003589 Al
`2001/0014665 Al
`2001/0036449 Al
`2002/0012680 Al
`2002/0013272 Al
`2002/0016290 Al
`2002/0016292 Al
`2002/0025927 Al
`2002/0045601 Al
`2002/0107183 Al
`2002/0119190 Al
`2002/0165134 Al
`2003/0021816 Al
`2003/0044452 Al
`2003/0055028 Al
`2003/0059470 Al
`2003/0060402 Al
`2003/0087813 Al
`2003/0104992 Al
`2003/0108626 Al
`2003/0109425 Al
`2003/0109426 Al
`2003/0133984 Al
`2003/0143250 Al
`2003/0147954 Al
`
`4/1999 Ishida et al.
`6/1999 Hauer et al.
`7/1999 Hamied et al.
`9/1999 Kawashima et al.
`10/1999 Hauer et al.
`10/1999 Hauer et al.
`10/1999 Cho et al.
`11/1999 Cavanak
`11/1999 Ko et al.
`11/1999 Ding et al.
`12/1999 Sherman
`12/1999 Friedman et al.
`12/1999 Hauer et al.
`12/1999 Singh
`12/1999 Al-Razzak et al.
`2/2000 Klokkers et al.
`2/2000 Hauer et al.
`4/2000 Stuchlik et al.
`5/2000 Mulye
`12/2000 Sherman
`3/2001 Sherman
`7/2001 Garst
`7/2001 Cho et al.
`7/2001 Chen et al.
`9/2001 Mishra et al.
`9/2001 Patel et al.
`10/2001 Cavanak
`11/2001 Burke
`2/2002 Singh et al.
`2/2002 Garst
`7/2002 Bennett et al.
`7/2002
`Richter et al.
`10/2002
`Cavanak et al.
`11/2002 Meinzer et al.
`11/2002 Olbrich et al.
`4/2003 Tsuzuki et al.
`4/2003 Matsuo
`5/2003 Olejnik et al.
`5/2003 Patel et al.
`6/2003 Kawashima
`12/2003
`Benita et al.
`3/2005
`Lyons
`1/2006 Bakhit et al. (cid:9)
`4/2007 Chang
`10/2007 Chang et al.
`10/2007 Chang et al.
`11/2007 Chang
`3/2009 Tien et al.
`7/2012 Chang et al.
`10/2012 Chang et al.
`6/2001 Neuer et al.
`8/2001 Fischer et al.
`11/2001
`Garst
`1/2002
`Patel et al.
`1/2002 Cavanak et al.
`2/2002 Floch'h et al.
`2/2002 Richter et al.
`2/2002 Olbrich et al.
`4/2002 Kawashima et al.
`8/2002 Petszulat et al.
`8/2002 Meinzer et al.
`11/2002 Richter et al.
`1/2003 Kang et al.
`3/2003
`Ueno
`3/2003
`Stergiopoulos et al.
`3/2003
`Muller
`3/2003 Cavanak et al.
`5/2003 Or et al.
`6/2003 Or et al.
`6/2003 Benita et al.
`6/2003 Or et al.
`6/2003 Or et al.
`7/2003 Ambuhl et al.
`7/2003 Hauer et al.
`8/2003 Yang et al.
`
` 514/20.8
`
`2003/0166517 Al (cid:9)
`2005/0014691 Al (cid:9)
`2005/0059583 Al (cid:9)
`2007/0015691 Al (cid:9)
`2007/0027072 Al (cid:9)
`2007/0087962 Al (cid:9)
`2007/0149447 Al (cid:9)
`2007/0299004 Al (cid:9)
`2008/0039378 Al (cid:9)
`2008/0070834 Al (cid:9)
`2008/0146497 Al (cid:9)
`2008/0207495 Al (cid:9)
`2009/0131307 Al (cid:9)
`2010/0279951 Al (cid:9)
`2011/0009339 Al (cid:9)
`2011/0294744 Al (cid:9)
`2012/0270805 Al (cid:9)
`2013/0059796 Al (cid:9)
`
`9/2003 (cid:9) Fricker et al.
`1/2005 (cid:9) Bakhit et al.
`3/2005 (cid:9) Acheampong et al.
`1/2007 (cid:9) Chang
`2/2007 (cid:9) Tien et al.
`4/2007 (cid:9) Tien et al.
`6/2007 (cid:9) Chang et al.
`12/2007 (cid:9) Acheampong et al.
`2/2008 (cid:9) Graham et al.
`3/2008 (cid:9) Chang et al.
`6/2008 (cid:9) Graham et al.
`8/2008 (cid:9) Graham et al.
`5/2009 (cid:9) Tien et al.
`11/2010 (cid:9) Morgan et al.
`1/2011 (cid:9) Schiffman
`12/2011 (cid:9) Morgan et al.
`10/2012 (cid:9) Chang et al.
`3/2013 (cid:9) Chang et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP (cid:9)
`EP (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`
`0547229 (cid:9)
`0760237 (cid:9)
`95-31211 (cid:9)
`00-00179 (cid:9)
`01-32142 (cid:9)
`01-41671 (cid:9)
`02-09667 (cid:9)
`02-49603 (cid:9)
`03-030834 (cid:9)
`03-053405 (cid:9)
`
`1/1993
`3/1997
`11/1995
`1/2000
`5/2001
`6/2001
`2/2002
`6/2002
`4/2003
`7/2003
`
`OTHER PUBLICATIONS
`Akpek, Esen Karamursel et al, A Randomized Trial of Topical
`Cyclosporin (cid:9)
`0.05% (cid:9)
`in (cid:9)
`Topical (cid:9)
`Steroid-Resistant (cid:9) Atopic
`Keratoconjunctivitis, Ophthalmology, 2004, 476-482, 111.
`Angelov, 0. et al, Preclinical Safety Studies of Cyclosporine
`Ophthalmic Emulsion, Adv Exp Med Biol, 1998, 991-995, 438.
`Angelov, 0. et al, Safety Assessment of Cyclosporine Ophthalmic
`Emulsion in Rabbits and Dogs, XIth Congress of the European Soci-
`ety of Ophthalmology, 1997, 25-28, 1-5, Soc. Ophthalmol Eur., HU.
`Ardizzone, Sandro et al, A Practical Guide to the Management of
`Distal Ulcerative Colitis, Drugs, 1998, 519-542, 55(4).
`Banic, Marko et al, Effect of Cyclosporine in a Murine Model of
`Experimental Colitis, Digestive Diseases and Sciences, Jun. 2002,
`1362-1368, 47(6).
`Bonini, S. et al, Vernal Keratoconjunctivitis, Eye, 2004, 345-351, 18.
`Brewster, Marcus et al, Enhanced Delivery of Ganciclovir to the
`Brain Through the Use of Redox Targeting, Antimicrobial Agents
`and Chemotherapy, Apr. 1994, 817-823, 38(4).
`Brewster, Marcus et al, Intravenous and Oral Pharmacokinetic Evalu-
`ation of a 2-Hydroxypropy1-13-cyclodextrin-Based Formulation of
`Carbamazepine in the Dog: Comparison with Commercially Avail-
`able Tablets and Suspensions, Journal of Pharmaceutical Sciences,
`Mar. 1997, 335-339, 86(3).
`Brewster, Marcus et al, Preparation, Characterization, andAnesthetic
`Properties (cid:9) of (cid:9) 2-Hydroxypropy1-13-cyclodextrin (cid:9) Complexes (cid:9) of
`Pregnanolone and Pregnenolone in Rat and Mouse, Journal of Phar-
`maceutical Sciences, Oct. 1995, 1154-1159, 84(10).
`Brinkmeier, Thomas et al, Pyodermatitis-Pyostomatitis Vegetans: a
`Clinical Course of Two Decades with Response to Cyclosporine and
`Low-Dose Prednisolone, Acta Derm Venereol, 2001, 134-136, 81.
`Castillo, Jose M. Benitez Del et al, Influence of Topical Cyclosporine
`A and Dissolvent on Corneal Epithelium Permeability of Fluores-
`cein, Documenta Ophthalmologica, 1995, 49-55, 91.
`Cheeks, Lisa et al, Influence ofVehicle and Anterior Chamber Protein
`Concentration on Cyclosporine Penetration Through the Isolated
`Rabbit Cornea, Current Eye Research, 1992, 641-649, 11(7).
`Database WPI Week 200044, Derwent Pub. Ltd., London, GB; An
`2000-492678 & JP2000/143542, 2000, 2 Pages.
`Ding, Shulin et al, Cyclosporine Ophthalmic 0/W emulsion: Formu-
`lation and Emulsion Characterization, Pharm Res, 1997, 1 page, 14
`(11).
`Donnenfeld, Eric D., The Economics of Using Restasis, Ophthalmol-
`ogy Management, Oct. 2003, 3 pages, US.
`
`
`
`US 8,648,048 B2
`Page 3
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Drosos, A. A. et al, Efficacy and Safety of Cyclosporine-A Therapy
`for Primary Sjogren's Syndrome, Ter. Arkh., 1998, 77-80, 60(4).
`Drosos, A.A. et al, Cyclosporin A Therapy in Patients with Primary
`Sjogren's Syndrome: Results at One Year, Scand J Rheumatology,
`1986, 246-249, 61.
`Eisen, Drore et al, Topical Cyclosporine for Oral Mucosal Disorders,
`J Am Acad Dermatol, Dec. 1990, 1259-1264, 23.
`Epstein, Joel et al, Topical Cyclosporine in a Bioadhesive for Treat-
`ment of Oral Lichenoid Muscosal Reactions, Oral Surg Oral Med
`Oral Pathol Oral, 1996, 532-536, 82.
`Erdmann, S. et al, Pemphigus Vulgaris Der Mund-Und
`Kehlkopfschleimhaut Pemphigus Vulgaris of the Oral Mucosa and
`the Larynx, H+G Zeitschrift Fuer Hautkrankheiten, 1997, 283-286,
`72(4).
`FDA Concludes Restasis (Cyclosporine) Not Effective for Dry Eye
`(Jun. 18, 1999). Accessed online at http://www.dryeyeinfo.org/
`Restasis Cyclosporine.htm on Aug. 14, 2009. 1 Page.
`Gaeta, G.M. et al, Cyclosporin Bioadhesive Gel in the Topical Treat-
`ment of Erosive Oral Lichen Planus, International Journal of
`Immunopathology and Pharmacology, 1994, 125-132, 7(2).
`Gipson, Ilene et al, Character of Ocular Surface Mucins and Their
`Alteration in Dry Eye Disease, The Ocular Surface, Apr. 2004, 131-
`148, 2(2).
`Gremse, David et al, Ulcerative Colitis in Children, Pediatr Drugs,
`2002, 807-815, 4(12).
`Gunduz, Kaan et al, Topical Cyclosporin Treatment of
`Keratoconjunctivitis Sicca in Secondary Sjogren's Syndrome, Acta
`Ophthalmologica, 1994, 438-442, 72.
`http://web.archive.org/web/2001030625323/http://www. surfactant.
`coskr/surfactants/pegestershtml, 2001, 6 Pages, retrieved on Jul. 5,
`2008.
`Hunter, P.A. et al, Cyclosporin A Applied Topically to the Recipient
`Eye Inhibits Corneal Graft Rejection, Clin Exp Immunol, 1981,
`173-177, 45.
`Jumaa, Muhannad et al, Physicochemical Properties and Hemolytic
`Effect of Different Lipid Emulsion Formulations Using a Mixture of
`Emulsifiers, Pharmaceutica Acta Helvetiae, 1999, 293-301, 73.
`Kanai, A. et al, The Effect on the Cornea of Alpha Cyclodextrin
`Vehicle for Eye Drops, Transplantation Proceedings, Feb. 1989,
`3150-3152, vol. 21.
`Kanpolat, Ayfer et al, Penetration of Cyclosporin A into the Rabbit
`Cornea and Aqueous Humor after Topical Drop and Collagen Shield
`Administration, Cornea/External Disease, Apr. 1994, 119-122,
`20(2).
`Kaur, Rabinder et al, Solid Dispersions of Drugs in Polyocyethylene
`40 Stearate: Dissolution Rates and Physico-Chemical Interactions,
`Journal of Pharmacy and Pharmacology, Dec. 1979, 48P.
`Kuwano, Mitsuaki et al, Cyclosporine A Formulation Affects Its
`Ocular Distribution in Rabbits, Pharmaceutical Research, Jan. 2002,
`108-111, 19(1).
`Lambert Technologies Corp. Material Safety Data Sheet for
`LUMULSETM POE-40 MS KP, last revision Aug. 22, 2003. 3 pages.
`Leibovitz, Z. et al., Our Experience in Processing Maize (Corn) Germ
`Oil, Journal of the American Oil Chemists Society, Feb. 1983, 395-
`399, 80 (2), US.
`Lixin, Xie et al, Effect of Cyclosporine A Delivery System in Corneal
`Transplantation, Chinese Medical Journal, 2002, 110-113, 115 (1),
`US.
`Lopatin, D.E., Chemical Compositions and Functions of Saliva, Aug.
`24, 2001, 31 Pages.
`Lyons, R.T. et al, Influence of Three Emulsion Formulation Param-
`eters on the Ocular Bioavailability of Cyclosporine A in Albino
`Rabbits, Am Assoc Pharm Sci, 2000, 1 Page, 2(4).
`Pedersen, Anne Marie et al, Primary Sjogren's Syndrome: Oral
`Aspects on Pathogenesis, Diagnostic Criteria, Clinical Features and
`Approaches for Therapy, Expert Opin Pharma, 2001, 1415-1436,
`2(9).
`
`Phillips, Thomas et al, Cyclosporine Has a Direct Effect on the
`Differentiation of a Mucin-Secreting Cell Line, Journal of Cellular
`Physiology, 2000, 400-408, 184.
`Present, D.H. et al, Cyclosporine and Other Immunosuppressive
`Agents: Current and Future Role in the Treatment of Inflammatory
`Bowel Disease, American Journal of Gastroenterology, 1993, 627-
`630, 88(5).
`Restasis® Product Information Sheet, Allergan, Inc., 2009, 5 Pages.
`Restasis® Increasing Tear Production, Retrieved on Aug. 14, 2009,
`http://www.restasisprofessional.com/ clinical/clinical increasing.
`htm 3 pages.
`Robinson, N.A. et al, Desquamative Gingivitis: A Sign of
`Mucocutaneous Disorders -a Review, Australian Dental Journal,
`2003, 205-211, 48(4).
`Rudinger, J., Characteristics of the Amino Acids as Components of a
`Peptide Hormone Sequence, Peptide Hormones, 1976, 1-7.
`Sall, Kenneth et al, Two Multicenter, Randomized Studies of the
`Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Mod-
`erate to Severe Dry Eye Disease, Ophthalmology, 2000, 631-639,
`107.
`Sandborn, William et al, A Placebo-Controlled Trial of Cyclosporine
`Enemas for Mildly to Moderately Active Left-Sided Ulcerative
`Colitis, Gastroenterology, 1994, 1429-1435, 106.
`Sandborn, William et al, Cyclosporine Enemas for Treatment-Resis-
`tant, Mildly to Moderately Active, Left-Sided Ulcerative Colitis,
`American Journal of Gastroenterology, 1993, 640-645, 88(5).
`Schwab, Matthias et al, Pharmacokinetic Considerations in the Treat-
`ment of Inflammatory Bowel Disease, Clin Pharm, 2001, 723-751,
`60(10).
`Secchi, Antonio et al, Topical Use of Cyclosporine in the Treatment
`ofVernal Keratoconjunctivitis, American Journal of Ophthalmology,
`Dec. 1990, 641-645, 110.
`Small, Dave et al, The Ocular Pharmacokinetics of Cyclosporine in
`Albino Rabbits and Beagle Dogs, Ocular Drug Delivery and Metabo-
`lism, 1999, 54.
`Small, David et al, Blood Concentrations of Cyclosporin A During
`Long-Term Treatment With Cyclosporin A ophthalmic Emulsions in
`Patients with Moderate to Severe Dry Eye Disease, Journal of Ocular
`Pharmacology and Therapeutics, 2002, 411-418, 18(5).
`Smilek, Dawn et al, A Single Amino Acid Change in a Myelin Basic
`Protein Peptide Confers the Capacity to Prevent Rather Than Induce
`Experimental Autoimmune Encephalomyelitis, Proc. Natl. Acad.
`Sci., Nov. 1991, 9633-9637, 88.
`Stephenson, Michelle, The Latest Uses of Restasis, Review of Oph-
`thalmology, Dec. 30, 2005, 7 Pages, US.
`Stevenson, Dara et al, Efficacy and Safety of Cyclosporin A
`ophthalmic Emulsion in the Treatment of Moderate-to-Severe Dry
`Eye Disease, Ophthalmology, 2000, 967-974, 107.
`Tesavibul, N. et al, Topical Cyclosporine A (CsA) for Ocular Surface
`Abnormalities in Graft Versus Host Disease Patients, Invest
`Ophthalmol Vis Sci, Feb. 1996, S1026, 37(3).
`The Online Medical Dictionary, Derivative, Analog, Analogue,
`Xerostomia, accessed Jul. 7, 2005 and Jul. 13, 2005, 6 Pages.
`Tibell, A. et al., Cyclosporin A in Fat Emulsion Carriers: Experimen-
`tal Studies on Pharmacokinetics and Tissue Distribution, Pharmacol-
`ogy & Toxicology, 1995, 115-121, 76, US.
`Tsubota, Kazuo et al, Use of Topical Cyclosporin A in a Primary
`Sjogren's Syndrome Mouse Model, Invest Ophthalmol Vis Sci, Aug.
`1998, 1551-1559, 39(9).
`Van Der Reijden, Willy et al, Treatment of Oral Dryness Related
`Complaints (Xerostomia) in Sjogren's Syndrome, Ann Rheum Dis,
`1999, 465-473, 58.
`Winter, T.A. et al, Cyclosporin A Retention Enemas in Refractory
`Distal Ulcerative Colitis and Touchitis', Scand J Gastroenterol,
`1993, 701-704, 28.
`U.S. Appl. No. 13/967,189, filed Aug. 14, 2013.
`U.S. Appl. No. 13/976,179, filed Aug. 14, 2013.
`U.S. Appl. No. 13/961,818, filed Aug. 7, 2013.
`U.S. Appl. No. 13/967,163, filed Aug. 14, 2013.
`U.S. Appl. No. 13/961,808, filed Aug. 7, 2013.
`U.S. Appl. No. 13/961,828, filed Aug. 7, 2013.
`U.S. Appl. No. 13/916,835, filed Aug. 7, 2013.
`Re-Examination U.S. Appl. No. 90/009,944, filed Aug. 27, 2011.
`
`* cited by examiner
`
`
`
`US 8,648,048 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`5 (cid:9)
`
`This application is a continuation of copending U.S. appli-
`cation Ser. No. 13/961,835 filed Aug. 7, 2013, which is a
`continuation of copending U.S. application Ser. No. 11/897,
`177, filed Aug. 28, 2007, which is a continuation of U.S. 10
`application Ser. No. 10/927,857, filed Aug. 27, 2004, now
`abandoned, which claimed the benefit of U.S. Provisional
`Application No. 60/503,137 filed Sep. 15, 2003, which are
`incorporated in their entirety herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`25
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using com-
`positions including cyclosporin components. More particu- 20
`larly, the invention relates to methods including administer-
`ing to an eye of a human or animal a therapeutically effective
`amount of a cyclosporin component to provide a desired
`therapeutic effect, preferably a desired ophthalmic or ocular
`therapeutic effect. (cid:9)
`The use of cyclosporin-A and cyclosporin A derivatives to
`treat ophthalmic conditions has been the subject of various
`patents, for example Ding et al U.S. Pat. No. 5,474,979; Garst
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442,
`this disclosure of each of which is incorporated in its entirely 30
`herein by reference. In addition, cyclosporin A compositions
`used in treating ophthalmic conditions is the subject of a
`number of publications. Such publications include, for
`example, "Blood concentrations of cyclosporin a during
`long-term treatment with cyclosporin a ophthalmic emul- 35
`sions in patients with moderate to severe dry eye disease,"
`Small et al, J Ocul Pharmacol Ther, 2002 October, 18(5):411 -
`8; "Distribution of cyclosporin A in ocular tissues after topi-
`cal administration to albino rabbits and beagle dogs,"
`Acheampong et al, Curr Eye Res, 1999 February, 18(2):91- 40
`103b; "Cyclosporine distribution into the conjunctiva, cor-
`nea, lacrimal gland, and systemic blood following topical
`dosing of cyclosporine to rabbit, dog, and human eyes,"
`Acheampong et al, Adv Exp Med Biol, 1998, 438:1001-4;
`"Preclinical safety studies of cyclosporine ophthalmic emul- 45
`sion," Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`"Cyclosporin & Emulsion & Eye," Stevenson et al, Ophthal-
`mology, 2000 May, 107(5):967-74; and "Two multicenter,
`randomized studies of the efficacy and safety of cyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease. 50
`CsA Phase 3 Study Group," Sall et al, Ophthalmology, 2000
`April, 107(4):631-9. Each of these publications is incorpo-
`rated in its entirety herein by reference. In addition,
`cyclosporin A-containing oil-in-water emulsions have been
`clinically tested, under conditions of confidentiality, since the 55
`mid 1990's in order to obtain U.S. Food and Drug Adminis-
`tration (FDA) regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Pat. No. 5,474,979. Example 1 of
`this patent shows a series of emulsions in which the ratio of 60
`cyclosporin A to castor oil in each of these compositions was
`0.08 or greater, except for Composition B, which included
`0.2% by weight cyclosporin A and 5% by weight castor oil.
`The Ding et al patent placed no significance in Composition
`B relative to Compositions A, C and D of Example 1. (cid:9)
`Over time, it has become apparent that cyclo sporinA emul-
`sions for ophthalmic use preferably have less than 0.2% by
`
`65
`
`2
`weight of cyclosporin A. With cyclosporin A concentrations
`less than 0.2%, the amount of castor oil employed has been
`reduced since one of the functions of the castor oil is to
`solubilize the cyclosporin A. Thus, if reduced amounts of
`cyclosporin are employed, reduced amounts of castor oil are
`needed to provide effective solubilization of cyclosporin A.
`There continues to be a need for providing enhanced meth-
`ods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`SUMMARY OF THE INVENTION
`
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been dis-
`covered. Such methods provide substantial overall efficacy in
`providing desired therapeutic effects. In addition, other
`important benefits are obtained employing the present meth-
`ods. For example, patient safety is enhanced. In particular, the
`present methods provide for reduced risks of side effects
`and/or drug interactions. Prescribing physicians advanta-
`geously have increased flexibility in prescribing such meth-
`ods and the compositions useful in such methods, for
`example, because of the reduced risks of harmful side effects
`and/or drug interactions. The present methods can be easily
`practiced. In short, the present methods provide substantial
`and acceptable overall efficacy, together with other advan-
`tages, such as increased safety and/or flexibility.
`In one aspect of the present invention, the present methods
`comprise administering to an eye of a human or animal a
`composition in the form of an emulsion comprising water, a
`hydrophobic component and a cyclosporin component in a
`therapeutically effective amount of less than 0.1% by weight
`of the composition. The weight ratio of the cyclosporin com-
`ponent to the hydrophobic component is less than 0.08.
`It has been found that the relatively increased amounts of
`hydrophobic component together with relatively reduced, yet
`therapeutically effective, amounts of cyclosporin component
`provide substantial and advantageous benefits. For example,
`the overall efficacy of the present compositions, for example
`in treating dry eye disease, is substantially equal to an iden-
`tical composition in which the cyclosporin component is
`present in an amount of 0.1% by weight. Further, a relatively
`high concentration of hydrophobic component is believed to
`provide for a more quick or rapid breaking down or resolving
`of the emulsion in the eye, which reduces vision distortion
`which may be caused by the presence of the emulsion in the
`eye and/or facilitates the therapeutic effectiveness of the com-
`position. Additionally, and importantly, using reduced
`amounts of the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug interac-
`tions.
`In short, the present invention provides at least one advan-
`tageous benefit, and preferably a plurality of advantageous
`benefits.
`The present methods are useful in treating any suitable
`condition which is therapeutically sensitive to or treatable
`with cyclosporin components. Such conditions preferably are
`ophthalmic or ocular conditions, that is relating to or having
`to do with one or more parts of an eye of a human or animal.
`Included among such conditions are, without limitation, dry
`eye syndrome, phacoanaphylactic endophthalmitis, uveitis,
`vernal conjunctivitis, atopic kerapoconjunctivitis, corneal
`graft rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Cyclosporin has been found as effective in treating immune
`mediated keratoconjunctivitis sicca (KCS or dry eye disease)
`in a patient suffering therefrom. The activity of cyclosporine
`
`
`
`US 8,648,048 B2
`
`4
`3
`is as an immunosuppressant and in the enhancement or restor- (cid:9)
`of such other components include, without limitation, emul-
`ing of lacrimal gland tearing. Other conditions that can be (cid:9)
`sifier components, tonicity components, polyelectrolyte
`treated with cyclosporin components include an absolute or (cid:9)
`components, surfactant components, viscosity inducing com-
`partial deficiency in aqueous tear production (keratoconjunc- (cid:9)
`ponents, acids and/or bases to adjust the pH of the composi-
`tivitis sicca, or KCS). Topical administration to a patient's 5 tion, buffer components, preservative components and the
`tear deficient eye can increase tear production in the eye. The (cid:9)
`like. Components may be employed which are effective to
`treatment can further serve to correct corneal and conjuncti- (cid:9)
`perform two or more functions in the presently useful com-
`val disorders exacerbated by tear deficiency and KCS, such as (cid:9)
`positions. For example, components which are effective as
`corneal scarring, corneal ulceration, inflammation of the cor- (cid:9)
`both emulsifiers and surfactants may be employed, and/or
`nea or conjunctiva, filamentary keratisis, mucopurulent dis- 10 components which are effective as both polyelectrolyte com-
`charge and vascularization of the cornea. (cid:9)
`ponents and viscosity inducing components may be
`Employing reduced concentrations of cyclosporin compo- (cid:9)
`employed. The specific composition chosen for use in the
`nent, as in the present invention, is advantageously effective (cid:9)
`present invention advantageously is selected taking into
`to provide the blood of the human or animal under treatment (cid:9)
`account various factors present in the specific application at
`with reduced concentrations of cyclosporin component, pref-
`15 hand, for example, the desired therapeutic effect to be
`erably with substantially no detectable concentration of the (cid:9)
`achieved, the desired properties of the compositions to be
`cyclosporin component. The cyclosporin component concen- (cid:9)
`employed, the sensitivities of the human or animal to whom
`tration of blood can be advantageously measured using a (cid:9)
`the composition is to be administered, and the like factors.
`validated liquid chromatography/mass spectrometry-mass (cid:9)
`The presently useful compositions advantageously are
`spectrometry (VLC/MS-MS) analytical method, such as 20 ophthalmically acceptable. A composition, component or
`described elsewhere herein. (cid:9)
`material is ophthalmically acceptable when it is compatible
`In one embodiment, in the present methods the blood of the (cid:9)
`with ocular tissue, that is, it does not cause significant or
`human or animal has concentrations of cyclosporin compo- (cid:9)
`undue detrimental effects when brought into contact with
`nent of 0.1 ng/ml or less. (cid:9)
`ocular tissues.
`Any suitable cyclosporin component effective in the 25 (cid:9)
`Such compositions have pH's within the physiological
`present methods may be used. (cid:9)
`range of about 6 to about 10, preferably in a range of about 7.0
`Cyclosporins are a group of nonpolar cyclic oligopeptides (cid:9)
`to about 8.0 and more preferably in a range of about 7.2 to
`with known immunosuppressant activity. Cyclosporin A, (cid:9)
`about 7.6.
`along with several other minor metabolites, cyclosporin B
`The present methods preferably provide for an administer-
`through I, have been identified. In addition, a number of 30 ing step comprising topically administering the presently use-
`synthetic analogs have been prepared. (cid:9)
`ful compositions to the eye or eyes of a human or animal.
`In general, commercially available cyclosporins may con- (cid:9)
`Each and every feature described herein, and each and
`tain a mixture of several individual cyclosporins which all (cid:9)
`every combination of two or more of such features, is
`share a cyclic peptide structure consisting of eleven amino (cid:9)
`included within the scope of the present invention provided
`acid residues with a total molecular weight of about 1,200, but 35 that the features included in such a combination are not mutu-
`with different substituents or configurations of some of the (cid:9)
`ally inconsistent.
`amino acids. (cid:9)
`These and other aspects and advantages of the present
`The term "cyclosporin component" as used herein is (cid:9)
`invention are apparent in the following detailed description,
`intended to include any individual member of the cyclosporin (cid:9)
`example and claims.
`group and derivatives thereof, as well as mixtures of two or 40
`more individual cyclosporins and derivatives thereof. (cid:9)
`Particularly preferred cyclosporin components include,
`The present methods are effective for treating an eye of a
`without limitation, cyclosporin A, derivatives of cyclosporin
`human or animal. Such methods, in general, comprise admin-
`A and the like and mixtures thereof. Cyclosporin A is an
`especially useful cyclosporin component. (cid:9)
`45 istering, preferably topically administering, to an eye of a
`human or animal a cyclosporin component-containing emul-
`Any suitable hydrophobic component may be employed in
`the present invention. Advantageously, the cyclosporin com- (cid:9)
`sion. The emulsion contains water, for example U.S. pure
`ponent is solubilized in the hydrophobic component. The (cid:9)
`water, a hydrophobic component and a cyclosporin compo-
`hydrophobic component may be considered as comprising a (cid:9)
`nent in a therapeutically effective amount of less than 0.1% by
`discontinuous phase in the presently useful cyclosporin com- so weight of the emulsion. In addition, beneficial results have
`ponent-containing emulsions. (cid:9)
`been found when the weight ratio of the cyclosporin compo-
`The hydrophobic component preferably is present in the (cid:9)
`nent to the hydrophobic component is less than 0.08.
`emulsion compositions in an amount greater than about
`As noted above, the present administering step preferably
`0.625% by weight. For example, the hydrophobic component
`includes topically administering the emulsion to the eye of a
`may be pr